The broad, long-term objective of the proposed research is to elucidate the role of bile acids (BAs) in obesity and energy regulation. Obesity is a chronic condition of energy dysregulation. Understanding the science of obesity is key to the development of more effective medical therapies that can halt the pandemic of this often fatal, disabling, and costly disease. BAs are a structurally and physiologically diverse group of lipids that have recently been implicated in energy regulatory pathways. As an initial project in a new area of research, the focus will be on studying the effect of Roux-en-Y gastric bypass (RYGB) on BA levels. As a remarkably effective weight loss surgery that works via neurohumoral pathways to dramatically alter hunger, satiety, and energy balance, RYGB offers a unique opportunity to understand the pathophysiology of obesity. The overall hypothesis of the proposed research is that the profound physiological effects of RYGB are partially mediated by alterations in bile acid-dependent energy regulatory pathways. The overall aim is to determine the degree to which bile acids contribute to the therapeutic effects of this weight loss surgery. The first specific aim is to assess the extent to which RYGB alters circulating BA levels, which are readily accessible, likely markers of the enterohepatic BA pool. This will be done by measuring fasting and postprandial levels of the 15 main BAs via mass spectroscopy-liquid chromatography in 50 subjects before and after gastric bypass. The second specific aim is to reveal the degree to which observed changes in serum BA levels contribute to the observed post-surgical changes in hunger, satiety, and weight loss. This aim is two-fold. First, fasting and post-prandial circulating BA levels will be correlated to hunger, satiety, and body weight. Each of these variables will be measured at 3-month intervals following RYGB until weight loss is complete. Secondly, the observed BA changes after RYGB will be blocked or reversed by treating subjects with selected BAs or a BA sequestrant for 1-week periods before and after surgery. The effect of this intervention on hunger and satiety will be assessed. In accordance with the overall hypothesis, we predict that changes in anatomy and Gl physiology induced by RYGB lead to alterations in one or more circulating BA levels, that these alterations correlate with post-surgical outcomes, and that blocking or reversing the observed alterations blunt the therapeutic effects of the surgery. PUBLIC HEALTH RELEVANCE: The development of innovative targeted medical therapies for obesity is critical to the cure of the obesity pandemic and to the resolution of its overwhelming physical and economic burden. By beginning to investigate the role of bile acids in obesity, this project aims to shed light on the understanding of this scientifically complex, yet still obscure, disease.